RGD Reference Report - Downregulation of hepatic cytochrome P450 in chronic renal failure. - Rat Genome Database

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Downregulation of hepatic cytochrome P450 in chronic renal failure.

Authors: Leblond, F  Guevin, C  Demers, C  Pellerin, I  Gascon-Barre, M  Pichette, V 
Citation: Leblond F, etal., J Am Soc Nephrol. 2001 Feb;12(2):326-32.
RGD ID: 6903939
Pubmed: PMID:11158222   (View Abstract at PubMed)

Chronic renal failure (CRF) is associated with a decrease in drug metabolism. The mechanism remains poorly understood. The present study investigated the repercussions of CRF on liver cytochrome P450 (CYP450). Three groups of rats were defined: control, control paired-fed, and CRF. Total CYP450 activity, protein expression of several CYP450 isoforms as well as their mRNA, and the in vitro N-demethylation of erythromycin were assessed in liver microsomes. The regulation of liver CYP450 by dexamethasone and phenobarbital was assessed in CRF rats. Compared with control and control paired-fed rats, creatinine clearance was reduced by 60% (P: < 0.01) in CRF rats. Weight was reduced by 30% (P: < 0.01) in control paired-fed and CRF rats, compared with control animals. There was no difference in the CYP450 parameters between control and control paired-fed. Compared with control paired-fed rats, total CYP450 was reduced by 47% (P: < 0.001) in CRF rats. Protein expression of CYP2C11, CYP3A1, and CYP3A2 were considerably reduced (>40%, P: < 0.001) in rats with CRF. The levels of CYP1A2, CYP2C6, CYP2D, and CYP2E1 were the same in the three groups. Northern blot analysis revealed a marked downregulation in gene expression of CYP2C11, 3A1, and 3A2 in CRF rats. Although liver CYP450 was reduced in CRF, its induction by dexamethasone and phenobarbital was present. N-demethylation of erythromycin was decreased by 50% in CRF rats compared with control (P: < 0.001). In conclusion, CRF in rats is associated with a decrease in liver cytochrome P450 activity (mainly in CYP2C11, CYP3A1, and 3A2), secondary to reduced gene expression.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CYP2C9Humanend stage renal disease  ISOCyp2c11 (Rattus norvegicus) RGD 
Cyp2c11Ratend stage renal disease  IEP  RGD 
Cyp2c55Mouseend stage renal disease  ISOCyp2c24 (Rattus norvegicus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cyp2c11  (cytochrome P450, subfamily 2, polypeptide 11)

Genes (Mus musculus)
Cyp2c55  (cytochrome P450, family 2, subfamily c, polypeptide 55)

Genes (Homo sapiens)
CYP2C9  (cytochrome P450 family 2 subfamily C member 9)


Additional Information